SUMMARY Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality in children and adults. Despite years of research, pharmacologic treatment has proven ineffective in decreasing mortality and morbidity which is likely due, in part, to heterogeneity in ARDS patients. Latent class analyses (LCA) of data from multiple large funded adult studies have identified two ARDS endotypes (subphenotypes) with differing clinical outcomes and response to treatment. There are no studies examining whether endotypes exist in pediatric ARDS (PARDS). However, by examining genome-wide gene expression in whole blood, endotypes have been identified in children with septic shock, another condition with a high degree of patient heterogeneity which involves dysregulation of the inflammatory/immune systems. The endotypes identified using this transcriptomic approach have differing risks of mortality and expression of immune inflammatory genes. Transcriptomics have not yet been used to define subgroups of adult or pediatric patients with ARDS. The PROSpect trial (UG3 HL141736) is an unprecedented opportunity to use biological samples from children with PARDS to answer several high impact questions related to PARDS heterogeneity. Our central hypothesis is that there are endotypes in children with PARDS which differ in their underlying pathophysiology and responsiveness to therapies. The goal of this proposal is to a) identify and characterize endotypes in children with PARDS using both LCA (Sp Aim 1) and gene expression profiling (Sp Aim 2) approaches, b) determine whether subgroups differ in outcome and/or response to treatment, and c) identify potential pathways involved in differences between endotype outcomes and response to treatment (Sp Aim 3). This proposal addresses one of the objectives in the strategic vision of the NHLBI, ?Identifying factors that account for individual differences in pathobiology and responses to treatment?. Our Specific Aims will test the hypotheses that: 1) LCA will identify two endotypes in children with PARDS, and that outcomes, and response to treatment, will vary between endotypes; 2) The two endotypes distinguished by the expression of 100 genes in children with septic shock also exist in children with PARDS, that de novo genome-wide expression profiling will identify additional endotypes in children with PARDS and, that outcomes and response to treatment will vary between transcriptomic endotypes identified using each approach; 3) Combining the results of the LCA with data on gene expression used for identification of transcriptomic endotypes will allow further stratification of patients with PARDS, and will reveal a subset of genes that are related to differential outcomes and response to treatment. This proposal will lay the fundamental groundwork for future precision care of PARDS patients by identifying: different endotypes within PARDS, differences in the underlying pathophysiology of PARDS endotypes, whether endotypes respond differently to treatment, and how endotypes of pediatric sepsis and PARDS relate to each other.